Project 2: Novel NeurosERMs and NeurosARMs for Protection Against Alzheimer Pathology Roberta Diaz Brinton, PhD, PI and Christian J. Pike, PhD, PI Our goal is to develop safe and efficacious alternative hormone therapies to prevent or delay late-onset age-associated Alzheimer's disease (AD). This proposal builds on our extensive knowledge of the mechanisms of estrogen and androgen action in brain and the extensive epidemiological data indicating that estrogen-based hormone therapy reduces the risk of developing AD and the emerging findings that androgen therapy can sustain cognitive function during aging. Basic science analyses of gonadal hormone action in neurons provide a mechanistic understanding for the healthy cell bias of hormone action. Studies proposed herein are a preclinical plan to translate our basic understanding of gonadal hormone mechanisms in brain into rationally designed molecules that will function as brain selective estrogen receptor modulators (NeurosERMs) and androgen receptor modulators (NeurosARMs). The proposed translational analyses build on several decades of basic science discovery that have established the solid foundation of predictive gonadal hormone outcomes in brain. It is on this foundation that we propose to develop innovative, safe and efficacious alternatives to hormone therapy to sustain neurological health and to prevent the dysfunction and pathology of late-onset age-associated AD. Specific Aim I proposes in vitro screens of NeurosERM and NeurosARM candidate molecules for efficacy to induce markers of neuroprotection, neural defense, neural plasticity. Further, we will assess the ability of candidate NeurosERMs and NeurosARMs to reduce B-amyloid accumulation and tau hyperphosphorylation. Consistent with the mission of the USC ADRC, we will also evaluate indicators of vascular viability and integrity to access efficacy of NeurosERMs / sARMs to prevent vascular disease. Molecules that reach criterion for in vitro efficacy will move to in vivo testing in Aim II. In Specific Aim II, we will evaluate efficacies of NeurosERM and NeurosARM candidate molecules in a transgenic mouse model of AD to 1) reduce levels of tau phosphorylation and B-amyloid accumulation; 2) prevent cognitive deficits; 3) protect against vascular injury; and 4) prevent proliferation in reproductive tissues.